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Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: strain differences in pathogenesis and host interferon response.

ABSTRACT: The Adames strain of Punta Toro virus (PTV-A, Bunyaviridae, Phlebovirus) causes an acute lethal disease in hamsters and mice. The Balliet strain of the virus (PTV-B) is generally considered to be avirulent. The difference in hamster susceptibility is likely due to the ability of PTV-A to suppress interferon (IFN)-beta similarly to that described for Rift Valley fever virus. Here we investigated strain differences in PTV pathogenesis and the IFN response in mice. Although PTV-B infection in mice did not induce systemic IFN-beta release, primary macrophages produced dramatically higher levels when exposed to the virus in culture. The importance of IFN in resistance to PTV infection was borne out in studies employing STAT-1 knock-out mice. Also, a number of genes specific to IFN response pathways were upregulated in PTV-B-infected macrophages. Our findings provide new insights into the type I IFN response during PTV infection in the mouse model of phleboviral disease.

SUBMITTER: Mendenhall M

PROVIDER: S-EPMC2783532 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: strain differences in pathogenesis and host interferon response.

Mendenhall Michelle M Wong Min-Hui MH Skirpstunas Ramona R Morrey John D JD Gowen Brian B BB

Virology 20090926 1

The Adames strain of Punta Toro virus (PTV-A, Bunyaviridae, Phlebovirus) causes an acute lethal disease in hamsters and mice. The Balliet strain of the virus (PTV-B) is generally considered to be avirulent. The difference in hamster susceptibility is likely due to the ability of PTV-A to suppress interferon (IFN)-beta similarly to that described for Rift Valley fever virus. Here we investigated strain differences in PTV pathogenesis and the IFN response in mice. Although PTV-B infection in mice ...[more]

PMID: 19783024

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Project description:Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) is a mosquito-borne zoonotic pathogen which can cause hemorrhagic fever, neurological disorders or blindness in humans, and a high rate of abortion in ruminants. MP-12 strain, a live-attenuated candidate vaccine, is attenuated in the M- and L-segments, but the S-segment retains the virulent phenotype. MP-12 was manufactured as an Investigational New Drug vaccine by using MRC-5 cells and encodes a functional NSs gene, the major virulence factor of RVFV which 1) induces a shutoff of the host transcription, 2) inhibits interferon (IFN)-? promoter activation, and 3) promotes the degradation of dsRNA-dependent protein kinase (PKR). MP-12 lacks a marker for differentiation of infected from vaccinated animals (DIVA). Although MP-12 lacking NSs works for DIVA, it does not replicate efficiently in type-I IFN-competent MRC-5 cells, while the use of type-I IFN-incompetent cells may negatively affect its genetic stability. To generate modified MP-12 vaccine candidates encoding a DIVA marker, while still replicating efficiently in MRC-5 cells, we generated recombinant MP-12 encoding Punta Toro virus Adames strain NSs (rMP12-PTNSs) or Sandfly fever Sicilian virus NSs (rMP12-SFSNSs) in place of MP-12 NSs. We have demonstrated that those recombinant MP-12 viruses inhibit IFN-? mRNA synthesis, yet do not promote the degradation of PKR. The rMP12-PTNSs, but not rMP12-SFSNSs, replicated more efficiently than recombinant MP-12 lacking NSs in MRC-5 cells. Mice vaccinated with rMP12-PTNSs or rMP12-SFSNSs induced neutralizing antibodies at a level equivalent to those vaccinated with MP-12, and were efficiently protected from wild-type RVFV challenge. The rMP12-PTNSs and rMP12-SFSNSs did not induce antibodies cross-reactive to anti-RVFV NSs antibody and are therefore applicable to DIVA. Thus, rMP12-PTNSs is highly efficacious, replicates efficiently in MRC-5 cells, and encodes a DIVA marker, all of which are important for vaccine development for Rift Valley fever.

Dataset Information

Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: strain differences in pathogenesis and host interferon response.

Publications

Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: strain differences in pathogenesis and host interferon response.

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